Benzenedicarboxylic acid derivatives

ABSTRACT

New benzenedicarboxylic acid derivative compounds; pharmaceutical compositions, diagnostic methods, and diagnostic kits that include those compounds; and methods of using those compounds for inhibiting NAALADase enzyme activity, detecting diseases where NAALADase levels are altered, effecting neuronal activity, effecting TGF-β activity, inhibiting angiogenesis, and treating glutamate abnormalities, neuropathy, pain, compulsive disorders, prostate diseases, cancers, and glaucoma.

This application is a divisional of U.S. patent application Ser. No.09/866,758, filed on May 30, 2001 now U.S. Pat. No. 6,452,044, which isa non-provisional of U.S. Provisional Patent Application No. 60/207,402,filed May 30, 2000, incorporated herein by reference in their entirety.

The present invention relates to new compounds, pharmaceuticalcompositions comprising such compounds, and methods of using suchcompounds to inhibit NAALADase enzyme activity, detecting diseases whereNAALADase levels are altered, inhibit angiogenesis, effect neuronalactivity, and treat glutamate abnormalities, neuropathy, pain, prostatediseases, cancers, TGF-β abnormalities, compulsive disorders, andglaucoma.

The NAALADase enzyme, also known as prostate specific membrane antigen(“PSM” or “PSMA”) and human glutamate carboxypeptidase II (“GCP II”),catalyzes the hydrolysis of the neuropeptide N-acetyl-aspartyl-glutamate(“NAAG”) to N-acetyl-aspartate (“NAA”) and glutamate. Based upon aminoacid sequence homology, NAALADase has been assigned to the M28 family ofpeptidases.

Studies suggest NAALADase inhibitors may be effective in treatingischemia, spinal cord injury, demyelinating diseases, Parkinson'sdisease, Amyotrophic Lateral Sclerosis (“ALS”), alcohol dependence,nicotine dependence, cocaine dependence, cancer, diabetic neuropathy,pain and schizophrenia, and in inhibiting angiogenesis. In view of theirbroad range of potential applications, a need exists for new NAALADaseinhibitors and pharmaceutical compositions comprising such compounds.

SUMMARY OF THE INVENTION

Specifically, the present invention relates to a compound of formula I

or a pharmaceutically acceptable equivalent, wherein:

-   -   X is —W—Z;    -   W is a bond or a linking group;    -   Z is a terminal group; and    -   Y is —COOH oriented meta or para relative to C-1.

Additionally, the present invention relates to a method for inhibitingNAALADase enzyme activity, treating a glutamate abnormality, effecting aneuronal activity (e.g., treating peripheral neuropathy or neuropathicpain), treating a prostate disease, treating cancer, inhibitingangiogenesis, or effecting a TGF-β activity, comprising administering toa mammal in need of such inhibition, treatment, or effect, an effectiveamount of a compound of formula I, as described above.

The present invention further relates to method for detecting a disease,disorder, or condition where NAALADase levels are altered, comprising:

-   -   (i) contacting a sample of bodily tissue or fluid with a        compound of formula I, as defined above, wherein said compound        binds to any NAALADase in said sample; and    -   (ii) measuring the amount of any NAALADase bound to said sample,        wherein the amount of NAALADase is diagnostic for said disease,        disorder or condition.

The present invention further relates to a method for detecting adisease, disorder or condition where NAALADase levels are altered in ananimal or a mammal, comprising:

-   -   (i) labeling a compound of formula L as defined above, with an        imaging reagent;    -   (ii) administering to said animal or mammal an effective amount        of the labeled compound;    -   (iii) allowing said labeled compound to localize and bind to        NAALADase present in said animal or mammal; and    -   (iv) measuring the amount of NAALADase bound to said labeled        compound, wherein the amount of NAALADase is diagnostic for said        disease, disorder or condition.

The present invention further relates to a diagnostic kit for detectinga disease, disorder or condition where NAALADase levels are altered,comprising a compound of formula I, as defined above, labeled with amarker.

The invention further relates to a pharmaceutical compositioncomprising:

-   -   (i) an effective amount of a compound of formula I or a        pharmaceutically acceptable equivalent; and    -   (ii) a pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a bar graph showing the effect of Compound C on TGF-β1concentrations in ischemic cell cultures.

FIG. 2 is a bar graph showing the effect of Compound C on TGF-β2concentrations in ischemic cell cultures.

FIG. 3 is a bar graph showing the reversal of the neuroprotective effectof Compound C by TGF-β neutralizing antibodies in ischemic cellcultures.

FIG. 4 is a bar graph showing the non-reversal of the neuroprotectiveeffect of Compound C by FGF neutralizing antibodies in ischemic cellcultures.

FIG. 5 is a bar graph showing the reversal of the neuroprotective effectof Compound C by TGF-β neutralizing antibodies in rats subjected tomiddle cerebral artery occlusion (“MCAO”).

FIG. 6 is a bar graph showing the effect of Compound C on TGF-β1 levelsduring occlusion and reperfusion in rats subjected to MCAO.

FIG. 7 is a graph plotting withdrawal latency of diabetic rats againstthe days following treatment with Compound A.

FIG. 8 is a graph plotting the formalin-induced flinching behavior ofrats treated with a vehicle or Compound C against the time followingtreatment.

FIG. 9 is a bar graph plotting the acetic acid-induced writhing of ratstreated with various doses of Compound C or a vehicle.

FIG. 10 is a bar graph plotting the acetic acid-induced writhing of ratstreated with various doses of Compound A or a vehicle.

FIG. 11 is a bar graph plotting the acetic acid-induced writhing of ratstreated with various doses of Compound D or a vehicle.

FIG. 12 is a bar graph plotting the chronic constrictive injury-inducedhyperalgesia of rats treated with a vehicle or Compound C against thedays after dosing.

FIG. 13A is a bar graph plotting the withdrawal latency differencescores of non-diabetic rats and STZ-diabetic rats treated with a vehicleor Compound A, against the days following administration with STZ.

FIG. 13B is a bar graph plotting the withdrawal latency differencescores of non-diabetic rats and STZ-diabetic rats treated with a vehicleor Compound D, against the days following administration with STZ.

FIG. 14 is a bar graph plotting the withdrawal latency difference scoresof normal (unoperated) rats and chronic constrictive injury-induced ratstreated with a vehicle or Compound C, against the days followingsurgery.

FIG. 15A is a bar graph plotting the motor nerve conduction velocity ofnon-diabetic rats and STZ-diabetic rats treated with a vehicle orCompound A, against the weeks following administration with STZ.

FIG. 15B is a bar graph plotting the sensory nerve conduction velocityof non-diabetic rats and STZ-diabetic rats treated with a vehicle orCompound A, against the weeks following administration with STZ.

FIG. 16A is a bar graph plotting the motor nerve conduction velocity ofnon-diabetic rats and STZ-diabetic rats treated with a vehicle orCompound D, against the weeks following administration with STZ.

FIG. 16B is a bar graph plotting the sensory nerve conduction velocityof non-diabetic rats and STZ-diabetic rats treated with a vehicle orCompound D, against the weeks following administration with STZ.

FIG. 17 is a graph plotting the withdrawal latency of non-diabetic ratsand BB/W diabetic rats treated with a vehicle, Compound D, or CompoundA, against the weeks of treatment.

FIG. 18 is a graph plotting the nerve conduction velocity ofnon-diabetic rats and BB/W diabetic rats treated with a vehicle,Compound D, or Compound A, against the weeks of treatment.

DETAILED DESCRIPTION Definitions

“Compound A” refers to2-[[(2,3,4,5,6-pentafluorobenzyl)hydroxyphosphinyl]methyl]pentanedioicacid.

“Compound B” refers to 2-(3-sulfanylpropyl)pentanedioic acid.

“Compound C” refers to 2-(phosphonomethyl)pentanedioic acid (“PMPA”).

“Compound D” refers to 2-(2-sulfanylethyl)pentanedioic acid.

“Alkyl” refers to a branched or unbranched saturated hydrocarbon chaincomprising a designated number of carbon atoms. For example, C₁-C₉ alkylis a straight or branched hydrocarbon chain containing 1 to 9 carbonatoms, and includes but is not limited to substituents such as methyl,ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, n-pentyl,n-hexyl, and the like, unless otherwise indicated.

“Alkenyl” refers to a branched or unbranched unsaturated hydrocarbonchain comprising a designated number of carbon atoms. For example, C₂-C₉alkenyl is a straight or branched hydrocarbon chain containing 2 to 9carbon atoms having at least one double bond, and includes but is notlimited to substituents such as ethenyl, propenyl, iso-propenyl,butenyl, iso-butenyl, tert-butenyl, n-pentenyl, n-hexenyl, and the like,unless otherwise indicated.

“Alkoxy” refers to the group —OR wherein R is alkyl as herein defined.Preferably, R is a branched or unbranched saturated hydrocarbon chaincontaining 1 to 9 carbon atoms.

“Carbocycle” refers to a hydrocarbon, cyclic moiety having one or moreclosed ring(s) that is/are alicyclic, aromatic, fused and/or bridged.Examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclopentene, cyclohexene, cycloheptene, cycloctene,benzyl, naphthene, anthracene, phenanthracene, biphenyl and pyrene.

“Aryl” refers to an aromatic, hydrocarbon cyclic moiety having one ormore closed rings. Examples include, without limitation, phenyl, benzyl,naphthyl, anthracenyl, phenanthracenyl, biphenyl, furanyl, and pyrenyl.

“Heterocycle” refers to a cyclic moiety having one or more closed ringsthat is/are alicyclic, aromatic, fused and/or bridged, with one or moreheteroatoms (for example, sulfur, nitrogen or oxygen) in at least one ofthe rings. Examples include, without limitation, pyrrolidine, pyrrole,thiazole, thiophene, piperidine, pyridine, isoxazolidine and isoxazole.

“Heteroaryl” refers to an aromatic, cyclic moiety having one or moreclosed rings with one or more heteroatoms (for example, sulfur, nitrogenor oxygen) in at least one of the rings. Examples include, withoutlimitation, pyrrole, thiophene, pyridine and isoxazole.

“Linking group” refers to a moiety that connects the metal binding groupwith the benzene ring in the compound of formula I, without compromisingthe pharmacological or biological activity of the overall compound.

“Metal binding group” refers to a functional group capable ofinteracting with metal ion(s), such as Co²⁺, Ni²⁺, Mn²⁺, Cu² ⁺, Zn²⁺,Mg²⁺, Fe²⁺, Fe³⁺, or Al³⁺. Metal binding groups include withoutlimitation amines (e.g., ethylenediamine), aldehydes, ketones,carboxylic acids (e.g., ethylenediaminetetraacetic acid (“EDTA”)),thiols, phosphorus derivatives and hydroxamic acids.

“Derivative” refers to a substance produced from another substanceeither directly or by modification or partial substitution.

“Effective amount” refers to the amount required to inhibit NAALADaseenzyme activity, treat a glutamate abnormality, effect a neuronalactivity, treat diabetic neuropathy, pain, prostate disease, and cancer,inhibit angiogenesis, and treat a TGF-β abnormality, a compulsivedisorder, and glaucoma.

“Electromagnetic radiation” includes without limitation radiation havinga wavelength of 10⁻²⁰ to 10⁰ m. Examples include, without limitation,gamma radiation (10⁻²⁰ to 10⁻¹³ m), x-ray radiation (10⁻¹¹ to 10⁻⁹ m),ultraviolet light (10 nm to 400 nm), visible light (400 nm to 700 nm),infrared radiation (700 nm to 1.0 mm) and microwave radiation (1 mm to30 cm).

“Halo” refers to at least one fluoro, chloro, bromo, or iodo moiety.

“Isosteres” refer to elements, functional groups, substitutents,molecules or ions having different molecular formulae but exhibitingsimilar or identical physical properties. For example, tetrazole is anisostere of carboxylic acid because it mimics the properties ofcarboxylic acid even though they have different molecular formulae.Typically, two isosteric molecules have similar or identical volumes andshapes. Ideally, isosteric compounds should be isomorphic and able toco-crystallize. Other physical properties that isosteric compoundsusually share include boiling point, density, viscosity and thermalconductivity. However, certain properties may be different: dipolarmoments, polarity, polarization, size and shape since the externalorbitals may be hybridized differently. The term “isosteres” encompass“bioisosteres.”

“Bioisosteres” are isosteres that, in addition to their physicalsimilarities, share some common biological properties. Typically,bioisosteres interact with the same recognition site or produce broadlysimilar biological effects.

“Carboxylic acid isosteres” include without limitation directderivatives such as hydroxamic acids, acyl-cyanamides andacylsulfonamides; planar acidic heterocycles such as tetrazoles,mercaptoazoles, sulfinylazoles, sulfonylazoles, isoxazoles,isothiazoles, hydroxythiadiazoles and hydroxychromes; and nonplanarsulfur- or phosphorus-derived acidic functions such as phosphinates,phosphonates, phosphonamides, sulphonates, sulphonamides, andacylsulphonamides.

“Metabolite” refers to a substance produced by metabolism or by ametabolic process.

“NAAG” refers to N-acetyl-aspartyl-glutamate, an important peptidecomponent of the brain, with levels comparable to the major inhibitorneurotransmitter gamma-aminobutyric acid (“GABA”). NAAG isneuron-specific, present in synaptic vesicles and released upon neuronalstimulation in several systems presumed to be glutamatergic. Studiessuggest that NAAG may function as a neurotransmitter and/orneuromodulator in the central nervous system, or as a precursor of theneurotransmitter glutamate. In addition, NAAG is an agonist at group IImetabotropic glutamate receptors, specifically mGluR3 receptors; whenattached to a moiety capable of inhibiting NAALADase, it is expectedthat metabotropic glutamate receptor ligands will provide potent andspecific NAALADase inhibitors.

“NAALADase” refers to N-acetylated α-linked acidic dipeptidase, amembrane bound metallopeptidase which catabolizes NAAG toN-acetylaspartate (“NAA”) and glutamate (“GLU”):

NAALADase has been assigned to the M28 peptidase family and is alsocalled PSM, PSMA, or GCP II, EC number 3.4.17.21. It is believed thatNAALADase is a co-catalytic zinc/zinc metallopeptidase. NAALADase showsa high affinity for NAAG with a Km of 540 nM. If NAAG is a bioactivepeptide, then NAALADase may serve to inactivate NAAG's synaptic action.Alternatively, if NAAG functions as a precursor for glutamate, theprimary function of NAALADase may be to regulate synaptic glutamateavailability.

“Pharmaceutically acceptable carrier” refers to any carrier, diluent,excipient, wetting agent, buffering agent, suspending agent, lubricatingagent, adjuvant, vehicle, delivery system, emulsifier, disintegrant,absorbent, preservative, surfactant, colorant, flavorant, or sweetener,preferably non-toxic, that would be suitable for use in a pharmaceuticalcomposition.

“Pharmaceutically acceptable equivalent” includes, without limitation,pharmaceutically acceptable salts, hydrates, metabolites, prodrugs andisosteres. Many pharmaceutically acceptable equivalents are expected tohave the same or similar in vitro or in vivo activity as the compoundsof the invention.

“Pharmaceutically acceptable salt” refers to a salt of the inventivecompounds which possesses the desired pharmacological activity and whichis neither biologically nor otherwise undesirable. The salt can beformed with acids that include, without limitation, acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloridehydrobromide, hydroiodide, 2-hydroxyethane-sulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate,thiocyanate, tosylate and undecanoate. Examples of a base salt includeammonium salts, alkali metal salts such as sodium and potassium salts,alkaline earth metal salts such as calcium and magnesium salts, saltswith organic bases such as dicyclohexylamine salts,N-methyl-D-glucamine, and salts with amino acids such as arginine andlysine. The basic nitrogen-containing groups can be quarternized withagents including lower alkyl halides such as methyl, ethyl, propyl andbutyl chlorides, bromides and iodides; dialkyl sulfates such asdimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides suchas decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides;and aralkyl halides such as benzyl and phenethyl bromides.

“Prodrug” refers to a derivative of the inventive compounds thatundergoes biotransformation, such as metabolism, before exhibiting itspharmacological effect(s). The prodrug is formulated with theobjective(s) of improved chemical stability, improved patient acceptanceand compliance, improved bioavailability, prolonged duration of action,improved organ selectivity, improved formulation (e.g., increasedhydrosolubility), and/or decreased side effects (e.g., toxicity). Theprodrug can be readily prepared from the inventive compounds usingmethods known in the art, such as those described by Burger's MedicinalChemistry and Drug Chemistry, Fifth Ed., Vol. 1, pp. 172-178, 949-982(1995).

“Radiosensitizer” refers to a low molecular weight compound administeredto animals in therapeutically effective amounts to promote the treatmentof diseases that are treatable with electromagnetic radiation. Diseasesthat are treatable with electromagnetic radiation include, withoutlimitation, neoplastic diseases, benign and malignant tumors, andcancerous cells. Electromagnetic radiation treatment of other diseasesnot listed herein are also contemplated by the present invention.

“Inhibition,” in the context of enzymes, refers to reversible enzymeinhibition such as competitive, uncompetitive, and non-competitiveinhibition. Competitive, uncompetitive, and non-competitive inhibitioncan be distinguished by the effects of an inhibitor on the reactionkinetics of an enzyme. Competitive inhibition occurs when the inhibitorcombines reversibly with the enzyme in such a way that it competes witha normal substrate for binding at the active site. The affinity betweenthe inhibitor and the enzyme may be measured by the inhibitor constant,K_(i), which is defined as:$K_{i} = \frac{\lbrack E\rbrack\lbrack I\rbrack}{\lbrack{EI}\rbrack}$

wherein [E] is the concentration of the enzyme, [I] is the concentrationof the inhibitor, and [EI] is the concentration of the enzyme-inhibitorcomplex formed by the reaction of the enzyme with the inhibitor. Unlessotherwise specified, K_(i) as used herein refers to the affinity betweenthe inventive compounds and NAALADase.

“IC₅₀” is a related term used to define the concentration or amount of acompound that is required to cause a 50% inhibition of the targetenzyme.

“NAALADase inhibitor” refers to any compound that inhibits NAALADaseenzyme activity. Preferably, a NAALADase inhibitor exhibits a K_(i) ofless than 100 μM, more preferably less than 10 μM, and even morepreferably less than 1 μM, as determined using any appropriate assayknown in the art.

“Isomers” refer to compounds having the same number and kind of atoms,and hence the same molecular weight, but differing with respect to thearrangement or configuration of the atoms.

“Stereoisomers” are isomers that differ only in the arrangement of theatoms in space.

“Optical isomers” refer to diastereoisomers or enantiomers.

“Diastereoisomers” are stereoisomers that are not mirror images of eachother. Diastereoisomers occur in compounds having two or more asymmetriccarbon atoms; thus, such compounds have 2″ optical isomers, where n isthe number of asymmetric carbon atoms.

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. Enantiomers result from the presence of oneor more asymmetric carbon atoms in the compound (e.g., glyceraldehyde,lactic acid, sugars, tartaric acid, amino acids).

“Enantiomer-enriched” refers to a mixture in which one enantiomerpredominates.

“Racemic mixture” means a mixture containing equal amounts of individualenantiomers.

“Non-racemic mixture” is a mixture containing unequal amounts ofenantiomers.

“Angiogenesis” refers to the process whereby new capillaries are formed.“Inhibition” of angiogenesis may be measured by many parameters inaccordance with the present invention and, for instance, may be assessedby delayed appearance of neovascular structures, slowed development ofneovascular structures, decreased occurrence of neovascular structures,slowed or decreased severity of angiogenesis-dependent disease effects,arrested angiogenic growth, or regression of previous angiogenic growth.In the extreme, complete inhibition is referred to herein as prevention.In relation to angiogenesis or angiogenic growth, “prevention” refers tono substantial angiogenesis or angiogenic growth if none had previouslyoccurred, or no substantial further angiogenesis or angiogenic growth ifgrowth had previously occurred.

“Angiogenesis-dependent disease” includes, without limitation,rheumatoid arthritis, cardiovascular diseases, neovascular diseases ofthe eye, peripheral vascular disorders, dermatologic ulcers andcancerous tumor growth, invasion, and metastasis.

“Animal” refers to a living organism having sensation and the power ofvoluntary movement, and which requires for its existence oxygen andorganic food. Examples include, without limitation, members of thehuman, equine, porcine, bovine, murine, canine, or feline species. Inthe case of a human, an “animal” may also be referred to as a “patient.”

“Mammal” refers to a warm-blooded vertebrate animal.

“Anxiety” includes without limitation the unpleasant emotional stateconsisting of psychophysiological responses to anticipation of unreal orimagined danger, ostensibly resulting from unrecognized intrapsychicconflict. Physiological concomitants include increased heart rate,altered respiration rate, sweating, trembling, weakness, and fatigue;psychological concomitants include feelings of impending danger,powerlessness, apprehension, and tension. Dorland's Illustrated MedicalDictionary, 27th ed. (W.B. Saunders Co. 1988).

“Anxiety Disorder” includes without limitation mental disorders in whichanxiety and avoidance behavior predominate. Dorland 's IllustratedMedical Dictionary, 27th ed. (W.B. Saunders Co. 1988). Examples includewithout limitation panic attack, agoraphobia, panic disorder, acutestress disorder, chronic stress disorder, specific phobia, simplephobia, social phobia, substance induced anxiety disorder, organicanxiety disorder, obsessive compulsive disorder, post-traumatic stressdisorder, generalized anxiety disorder, and anxiety disorder NOS. Otheranxiety disorders are characterized in Diagnostic and Statistical Manualof Mental Disorders, 4th ed. (American Psychiatric Association 1994).

“Attention Deficit Disorder” (“ADD”) refers to a disorder characterizedby developmentally inappropriate inattention and impulsiveness, with orwithout hyperactivity. Inattention means a failure to finish tasksstarted, easily distracted, seeming lack of attention, and difficultyconcentrating on tasks requiring sustained attention. Impulsivenessmeans acting before thinking, difficulty taking turns, problemsorganizing work, and constant shifting from one activity to another.Hyperactivity means difficulty staying seated and sitting still, andrunning or climbing excessively.

“Cancer” includes, without limitation, ACTH-producing tumors, acutelymphocytic leukemia, acute nonlymphocytic leukemia, cancer of theadrenal cortex, bladder cancer, brain cancer, breast cancer, cervixcancer, chronic lymphocytic leukemia, chronic myelocytic leukemia,colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer,esophageal cancer, Ewing's sarcoma, gallbladder cancer, hairy cellleukemia, head and neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma,kidney cancer, liver cancer, lung cancer (small and/or non-small cell),malignant peritoneal effusion, malignant pleural effusion, melanoma,mesothelioma, multiple myeloma, neuroblastoma, non-Hodgkin's lymphoma,osteosarcoma, ovary cancer, ovary (germ cell) cancer, pancreatic cancer,penis cancer, prostate cancer, retinoblastoma, skin cancer, soft-tissuesarcoma, squamous cell carcinomas, stomach cancer, testicular cancer,thyroid cancer, trophoblastic neoplasms, cancer of the uterus, vaginalcancer, cancer of the vulva, and Wilm's tumor.

“Compulsive disorder” refers to any disorder characterized byirresistible impulsive behavior. Examples of compulsive disordersinclude without limitation drug dependence, eating disorders,pathological gambling, ADD, and Tourette's syndrome.

“Demyelinating disease” refers to any disease involving damage to orremoval of the myelin sheath naturally surrounding nerve tissue, such asthat defined in U.S. Pat. No. 5,859,046 and International PublicationNo. WO 98/03178, herein incorporated by reference. Examples includewithout limitation peripheral demyelinating diseases (such asGuillain-Barré syndrome, peripheral neuropathies and Charcot-Marie Toothdisease) and central demyelinating diseases (such as multiplesclerosis).

“Disease” refers to any deviation from or interruption of the normalstructure or function of any part, organ or system (or combinations) ofthe body that is manifested by a characteristic set of symptoms andsigns and whose etiology, pathology, and prognosis may be known orunknown. Dorland 's Illustrated Medical Dictionary, 27th ed. (W.B.Saunders Co. 1988).

“Disorder” refers to any derangement or abnormality of function; amorbid physical or mental state. Dorland 's Illustrated MedicalDictionary, 27th ed. (W.B. Saunders Co. 1988).

“Substance dependence” refers to a psychologic addiction or a physicaltolerance to a substance. Tolerance means a need to increase the doseprogressively in order to produce the effect originally achieved bysmaller amounts.

“Eating disorder” refers to compulsive overeating, obesity, or severeobesity. Obesity means body weight of 20% over standard height-weighttables. Severe obesity means over 100% overweight.

“Glaucoma” includes without limitation chronic (idiopathic) open-angleglaucomas (e.g., high-pressure, normal-pressure); pupillary blockglaucomas (e.g., acute angle-closure, subacute angle-closure, chronicangle-closure, combined-mechanism); developmental glaucomas (e.g.,congenital (infantile), juvenile, Anxenfeld-Rieger syndrome, Peters'anomaly, Aniridia); glaucomas associated with other ocular disorders(e.g., glaucomas associated with disorders of the corneal endothelium,iris, ciliary body, lens, retina, choroid and vitreous); glaucomasassociated with elevated episcleral venous pressure (e.g., systemicdiseases with associated elevated intraocular pressure and glaucoma,corticosteroid-induced glaucoma); glaucomas associated with inflammationand trauma (e.g., glaucomas associated with keratitis, episcleritis,scleritis, uveitis, ocular trauma and hemorrhage); glaucomas followingintraocular surgery, e.g., ciliary block (malignant) glaucoma, glaucomasin aphakia and pseudophakia, glaucomas associated with corneal surgery,glaucomas associated with vitreoretinal surgery.

“Glutamate abnormality” refers to any disease, disorder, or condition inwhich glutamate is implicated, including pathological conditionsinvolving elevated levels of glutamate. Examples of glutamateabnormalities include, without limitation, glaucoma, spinal cord injury,epilepsy, stroke, Alzheimer's disease, Parkinson's disease, ALS,Huntington's disease, schizophrenia, pain, ischemia, peripheralneuropathy (including but not limited to diabetic neuropathy), traumaticbrain injury, neuronal insult, inflammatory diseases, anxiety, anxietydisorders, memory impairment, and compulsive disorders.

“Ischemia” refers to localized tissue anemia due to obstruction of theinflow of arterial blood. Global ischemia occurs when blood flow ceasesfor a period of time, as may result from cardiac arrest. Focal ischemiaoccurs when a portion of the body, such as the brain, is deprived of itsnormal blood supply, such as may result from thromboembolytic occlusionof a cerebral vessel, traumatic head injury, edema or brain tumor. Evenif transient, both global and focal ischemia can produce widespreadneuronal damage. Although nerve tissue damage occurs over hours or evendays following the onset of ischemia, some permanent nerve tissue damagemay develop in the initial minutes following cessation of blood flow tothe brain. Much of this damage is attributed to glutamate toxicity andsecondary consequences of reperfusion of the tissue, such as the releaseof vasoactive products by damaged endothelium, and the release ofcytotoxic products, such as free radicals and leukotrienes, by thedamaged tissue.

“Memory impairment” refers to a diminished mental registration,retention or recall of past experiences, knowledge, ideas, sensations,thoughts or impressions. Memory impairment may affect short andlong-term information retention, facility with spatial relationships,memory (rehearsal) strategies, and verbal retrieval and production.Common causes of memory impairment are age, severe head trauma, brainanoxia or ischemia, alcoholic-nutritional diseases, drug intoxicationsand neurodegenerative diseases. For example, memory impairment is acommon feature of neurodegenerative diseases such as Alzheimer's diseaseand senile dementia of the Alzheimer type. Memory impairment also occurswith other kinds of dementia such as multi-infarct dementia, a seniledementia caused by cerebrovascular deficiency, and the Lewy-body variantof Alzheimer's disease with or without association with Parkinson'sdisease. Creutzfeldt-Jakob disease is a rare dementia with which memoryimpairment is associated. It is a spongiform encephalopathy caused bythe prion protein; it may be transmitted from other sufferers or mayarise from gene mutations. Loss of memory is also a common feature ofbrain-damaged patients. Brain damage may occur, for example, after aclassical stroke or as a result of an anaesthetic accident, head trauma,hypoglycemia, carbon monoxide poisoning, lithium intoxication, vitamin(B₁, thiamine, and B₁₂) deficiency, or excessive alcohol use.Korsakoff's amnesic psychosis is a rare disorder characterized byprofound memory loss and confabulation, whereby the patient inventsstories to conceal his or her memory loss. It is frequently associatedwith excessive alcohol intake. Memory impairment may furthermore beage-associated; the ability to recall information such as names, placesand words seems to decrease with increasing age. Transient memory lossmay also occur in patients, suffering from a major depressive disorder,after electro-convulsive therapy.

“Mental disorder” refers to any clinically significant behavioral orpsychological syndrome characterized by the presence of distressingsymptoms or significant impairment of functioning. Mental disorders areassumed to result from some psychological or organic dysfunction of theindividual; the concept does not include disturbances that areessentially conflicts between the individual and society (socialdeviance).

“Metastasis” refers to “[t]he ability of cells of a cancer todisseminate and form new foci of growth at noncontiguous sites (i.e., toform metastases).” See Hill, R. P, “Metastasis”, The Basic Science ofOncology, Tannock et al., Eds., pp. 178-195 (McGraw-Hill 1992), hereinincorporated by reference. “The transition from in situ tumor growth tometastatic disease is defined by the ability of tumor cells of theprimary site to invade local tissues and to cross tissue barriers . . .To initiate the metastatic process, carcinoma cells must first penetratethe epithelial basement membrane and then invade the interstitial stroma. . . For distant metastases, intravasation requires tumor cell invasionof the subendothelial basement membrane that must also be negotiatedduring tumor cell extravasation . . . The development of malignancy isalso associated with tumor-induced angiogenesis [which] not only allowsfor expansion of the primary tumors, but also permits easy access to thevascular compartment due to defects in the basement membranes of newlyformed vessels.” See Aznavoorian et al., Cancer (1993) 71:1368-1383,herein incorporated by reference.

“Nervous insult” refers to any damage to nervous tissue and anydisability or death resulting therefrom. The cause of nervous insult maybe metabolic, toxic, neurotoxic, iatrogenic, thermal or chemical, andincludes without limitation ischemia, hypoxia, cerebrovascular accident,trauma, surgery, pressure, mass effect, hemorrhage, radiation,vasospasm, neurodegenerative disease, neurodegenerative process,infection, Parkinson's disease, ALS, myelination/demyelinationprocesses, epilepsy, cognitive disorder, glutamate abnormality andsecondary effects thereof.

“Nervous tissue” refers to the various components that make up thenervous system, including without limitation neurons, neural supportcells, glia, Schwann cells, vasculature contained within and supplyingthese structures, the central nervous system, the brain, the brain stem,the spinal cord, the junction of the central nervous system with theperipheral nervous system, the peripheral nervous system and alliedstructures.

“Neuropathy” refers to any disease or malfunction of the nerves.Neuropathy includes, without limitation, peripheral neuropathy, diabeticneuropathy, autonomic neuropathy and mononeuropathy. Peripheralneuropathy may be idiopathic or induced by any causes including diseases(for example, amyloidosis, alcoholism, HIV, syphilis, virus, autoimmunedisorder, cancer, porphyria, arachnoiditis, post herpetic neuralgia,Guillain-Barré syndrome, diabetes including Type I and Type IIdiabetes), chemicals (for example, toxins, lead, dapsone, vitamins,paclitaxel chemotherapy, HAART therapy) and physical injuries to aparticular nerve or nerve plexus (for example, trauma, compression,constriction).

“Neuroprotective” refers to the effect of reducing, arresting orameliorating nervous insult, and protecting, resuscitating or revivingnervous tissue that has suffered nervous insult.

“Pain” refers to localized sensations of discomfort, distress or agony,resulting from the stimulation of specialized nerve endings. It servesas a protective mechanism insofar as it induces the sufferer to removeor withdraw from the source. Dorland 's Illustrated Medical Dictionary,27th ed. (W.B. Saunders Co. 1988). Examples of pain include, withoutlimitation, acute, chronic, cancer, bum, incisional, inflammatory,diabetic neuropathic, and back pain.

“Neuropathic pain” refers to a condition of pain associated with a nerveinjury. Depending on the particular syndrome, the pain may be due toalterations of the brain or spinal cord or may be due to abnormalitiesin the nerve itself. Neuropathic pain may be idiopathic or induced byany causes including diseases (for example, amyloidosis, alcoholism,HIV, syphilis, virus, autoimmune disorder, cancer, porphyria,arachnoiditis, post herpetic neuralgia, Guillain-Barré syndrome, anddiabetes, including Type I and Type II diabetes), chemicals (forexample, toxins, lead, dapsone, vitamins, paclitaxel chemotherapy, andHAART therapy) and physical injuries to a particular nerve or nerveplexus (for example, trauma, compression, and constriction).

“Pathological gambling” refers to a condition characterized by apreoccupation with gambling. Similar to psychoactive substance abuse,its effects include development of tolerance with a need to gambleprogressively larger amounts of money, withdrawal symptoms, andcontinued gambling despite severe negative effects on family andoccupation.

“Prostate disease” refers to any disease affecting the prostate.Examples of prostate disease include without limitation prostate cancersuch as adenocarcinoma and metastatic cancers of the prostate; andconditions characterized by abnormal growth of prostatic epithelialcells such as benign prostatic hyperplasia.

“Schizophrenia” refers to a mental disorder or group of mental disorderscharacterized by disturbances in form and content of thought (looseningof associations, delusions, hallucinations), mood (blunted, flattened,inappropriate affect), sense of self and relationship to the externalworld (loss of ego boundaries, dereistic thinking, and autisticwithdrawal), and behavior (bizarre, apparently purposeless, andstereotyped activity or inactivity). Examples of schizophrenia include,without limitation, acute, ambulatory, borderline, catatonic, childhood,disorganized, hebephrenic, latent, nuclear, paranoid, paraphrenic,prepsychotic, process, pseudoneurotic, pseudopsychopathic, reactive,residual, schizo-affective and indifferentiated schizophrenia. Dorland'sIllustrated Medical Dictionary, 27th ed. (W.B. Saunders Co. 1988).

“TGF-β” refers to transforming growth factor beta. TGF-β is recognizedas a prototype of multifunctional growth factors. It regulates variouscell and tissue functions, including cell growth and differentiation,angiogenesis, wound healing, immune function, extracellular matrixproduction, cell chemotaxis, apoptosis and hematopoiesis.

“TGF-β abnormality” refers to any disease, disorder or condition inwhich TGF-β is implicated, including diseases disorders and conditionscharacterized by an abnormal level of TGF-β.

“Abnormal level of TGF-β” refers to a measurable variance from normallevels of TGF-β, as determined by one of ordinary skill in the art usingknown techniques.

“Therapeutic window of opportunity” or “window” refers, in relation tostroke, to the maximal delay between the onset of stroke and theinitiation of efficacious therapy.

“Tourette's syndrome” refers to an autosomal multiple tic disordercharacterized by compulsive swearing, multiple muscle tics and loudnoises. Tics are brief, rapid, involuntary movements that can be simpleor complex; they are stereotyped and repetitive, but not rhythmic.Simple tics, such as eye blinking, often begin as nervous mannerisms.Complex tics often resemble fragments of normal behavior.

“Treating” refers to:

-   -   (i) preventing a disease, disorder or condition from occurring        in an animal that may be predisposed to the disease, disorder        and/or condition but has not yet been diagnosed as having it;    -   (ii) inhibiting the disease, disorder or condition, i.e.,        arresting its development; and/or    -   (iii) relieving the disease, disorder or condition, i.e.,        causing regression of the disease, disorder and/or condition.

“Treating substance dependence” refers to suppressing the psychologicaddiction or physical tolerance to the drug of abuse, and/or relievingand/or preventing a withdrawal syndrome resulting from the drugdependence.

“Dependence” refers to a maladaptive pattern of substance use, leadingto clinically significant impairment or distress. Dependence istypically characterized by tolerance and/or withdrawal. Substances forwhich dependence may be developed include, without limitation,depressants (opioids, synthetic narcotics, barbiturates, glutethimide,methyprylon, ethchlorvynol, methaqualone, alcohol); anxiolytics(diazepam, chlordiazepoxide, alprazolam, oxazepam, temazepam);stimulants (amphetamine, methamphetamine, cocaine); and hallucinogens(LSD, mescaline, peyote, marijuana).

“Tolerance” refers to an acquired reaction to a substance characterizedby diminished effect with continued use of the same dose and/or a needfor increased doses to achieve intoxication or desired effect previouslyachieved by lower doses. Both physiological and psychosocial factors maycontribute to the development of tolerance. With respect tophysiological tolerance, metabolic and/or functional tolerance maydevelop. By increasing the rate of metabolism of the substance, the bodymay be able to eliminate the substance more readily. Functionaltolerance is defined as a decrease in sensitivity of the central nervoussystem to the substance.

“Withdrawal” refers to a syndrome characterized by untoward physicalchanges that occur following cessation of or reduction in substance use,or administration of a pharmacologic antagonist.

One of ordinary skill in the art will recognize that there arealternative nomenclatures, nosologies and classification systems for thediseases, disorders and conditions defined above, and that such systemsevolve with medical scientific progress.

Unless the context clearly dictates otherwise, the definitions ofsingular terms may be extrapolated to apply to their plural counterpartsas they appear in the application; likewise, the definitions of pluralterms may be extrapolated to apply to their singular counterparts asthey appear in the application.

Compounds of the Invention

Specifically, the present invention relates to a compound of formula I

or a pharmaceutically acceptable equivalent, wherein:

-   -   X is —W—Z;    -   W is a bond or a linking group;    -   Z is a terminal group; and    -   Y is —COOH oriented meta or para relative to C-1.

Linking groups include without limitation divalent hydrocarbon chains,ethers, sulfides and amines, wherein the hydrocarbon chain, whetheralone or part of the ether, sulfide or amine, may be saturated orunsaturated, straight or branched, open or closed, unsubstituted orsubstituted with one or more substituent(s), preferably, independentlyselected from the group consisting of C₁-C₆ alkoxy, C₂-C₆ alkenyloxy,phenoxy, benzyloxy, hydroxy, carboxy, carbamido, carbamoyl, carbamyl,carbonyl, carbozoyl, amino, hydroxyamino, formamido, formyl, guanyl,cyano, cyanoamino, isocyano, isocyanato, diazo, azido, hydrazino,triazano, nitrilo, isonitrilo, nitro, nitroso, isonitroso, nitrosamino,imino, nitrosimino, oxo, C₁-C₆ alkylthio, sulfamino, sulfamoyl, sulfeno,sulfhydryl, sulfinyl, sulfo, sulfonyl, sulfoxy, thiocarboxy, thiocyano,isothiocyano, thioformamido, halo, haloalkyl, chlorosyl, chloryl,perchloryl, trifluoromethyl, iodosyl, iodyl, phosphino, phosphinyl,phospho, phosphono, arsino, selanyl, diselanyl, siloxy, silyl andsilylene.

Preferably, W is a bond, —(CR₁R₂)_(n)—, —(CR₁R₂)_(n)O(CR₃R₄)_(m)—,—(CR₁R₂)_(n)S(CR₃R₄)_(m)— or —(CR₁R₂)_(n)NR(CR₃R₄)_(m)—, wherein m and nare independently 0-9, and R, R₁, R₂, R₃ and R₄ are independentlyhydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₄ aryl,heteroaryl, C₆-C₁₄ carbocycle, heterocycle, halo, hydroxy, sulfhydryl,nitro, amino or C₁-C₆ alkoxy, and said alkyl, alkenyl, alkynyl, aryl,heteroaryl, carbocycle, heterocycle or alkoxy is independentlyunsubstituted or substituted with one or more substituent(s). Morepreferably, R, R₁, R₂, R₃ and R₄ are each hydrogen and the total numberof carbon atoms in W is 2-6.

Preferably, Z is a metal binding group. More preferably, Z is —COOH,—COR₅, —OR₅, —CF₃, —CN, —F, —Cl, —Br, —I, —NO, —NO₂, —C(O)(NR₅OR₆),—C(O)(NR₅PO₃H₂), —C(O)(NR₅R₆), ═NOH, —NR₅(P(O)(R₆)OH), ═NR₅, —N═NR₅,—N(R₅)CN, —NR(CR₆R₇)_(p)COOH, —NR₅(CO)NR₆R₇, —NR₅(COOR₆), —NR₅(CO)R₆,—NR₅(OR₆), —NR₅R₆, —NR₅(SO₂R₆), —O(CO)R₅, —OR₅, —SO₂(OR₅), —SO₂(NR₅R₆),—SO₂R₅, —SO₃R₅, —SNR₅(OR₆), —S(NR₅R₆), —SR₅, —SSR₅, —P(O)(OH)OR₅,—P(O)(OH)R₅ or —PR₅R₆, wherein p is 0-6, and R₅, R₆ and R₇ areindependently hydrogen, C₁-C₉ alkyl, C₂-C₉ alkenyl, C₂-C₉ alkynyl,C₆-C₁₄ aryl, heteroaryl, C₆-C₁₄ carbocycle, heterocycle, halo, hydroxy,sulfhydryl, nitro, amino or C₁-C₉ alkoxy, and said alkyl, alkenyl,alkynyl, aryl, heteroaryl, carbocycle, heterocycle or alkoxy isindependently unsubstituted or substituted with one or moresubstituent(s). More preferably, Z is —NH(CR₆R₇)_(p)COOH, —PO(OH)OR₅,—PO(OH)R₅, —NR₅(P(O)(OH)R₆), —CON(R₅)(OH) or —SH.

In a preferred embodiment of formula I, X is —SO₂-aryl, carboxy, S-aryl,nitro, halo, amino, —SO₃H, —(CR₁R₂)_(n)CO₂R₃, —NR₅(CR₁R₂)_(n)CO₂R₃,—(C═O)-aryl, —(C═O)-phenyoxy-aryl, —(C═O)N₅-aryl,—O(CR₁R₂)_(n)—S—S—(CR₃R₄)_(m)O-aryl, hydroxy,—(CR₁R₂)_(n)NR₅(CR₃R₄)_(m)-heteroaryl, —NR₅—(C═O)alkyl, andNR₅—(C═O)-aryl; wherein m and n are independently 0-9; R₁, R₂, R₃, R₄,and R₅ are independently hydrogen C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₆-C₁₄ aryl, heteoaryl, C₆-C₁₄ carbocycle, heterocycle, halo,hydroxy, sulfhydryl, nitro, amino or C₁-C₆ alkoxy; wherein said alkyl,alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle or alkoxy isindependently unsubstituted or substituted with one or moresubstituent(s).

In another preferred embodiment of formula I:

X is —(CR₁R₂)_(n)NH(CR₃R₄)_(m)COOH, —PO((OH)OR₅,—(CR₁R₂)_(n)P(O)(OH)OR₅, —NH—(CR₃R₄)_(m)-heteroaryl, —NH(P(O)(OH)R₆),—(CR₁R₂)_(n)NH(P(O)(OH)R₆), —CON(R₅)(OH), —(CR₁R₂)_(n)CON(R₅)(OH),—(CR₁R₂)_(n)SH, —O(CR₃R₄)_(m)SH, —SO₂NH-aryl,—NR₅(C═O)—(CR₁R₂)_(n)(C═O)-aryl, —SO₂NH-aryl-N(C═O)—CH₂(C═O)-aryl,—O-aryl wherein aryl in —O-aryl is substituted by at least one of nitroor carboxy, or

wherein X is oriented meta or para to C-1;

m and n are independently 1-3, provided that when X is —O(CR₃R₄)_(m)SH,then m is 2 or 3;

R₁, R₂, R₃, R₄, R₅, and R₆ are independently hydrogen, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₄ aryl, heteroaryl, C₆-C₁₄carbocycle, heterocycle, halo, hydroxy, sulfhydryl, nitro, amino orC₁-C₆ alkoxy, wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl,carbocycle, heterocycle or alkoxy is independently unsubstituted orsubstituted with one or more substituent(s); and

Y is —COOH oriented meta or para relative to C-1;

and preferably, when X is —PO(OH)OR₅ or —(CR₁R₂)_(n)P(O)(OH)OR₅, then R₅is not H or methyl; when X is —NH(P(O)(OH)R₆) or—(CR₁R₂)_(n)NH(P(O)(OH)R₆), then R₆ is not benzyl unsubstituted orsubstituted with amino; and when X is —CON(R₅)(OH), then R₅ is not H ormethyl.

Possible substituents of said alkyl, alkenyl, alkynyl, aryl, heteroaryl,carbocycle, heterocycle and alkoxy include, without limitation, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₂-C₆ alkenyloxy,phenoxy, benzyloxy, hydroxy, carboxy, hydroperoxy, carboxy, carbamido,carbamoyl, carbamyl, carbonyl, carbozoyl, amino, hydroxyamino,formamido, formyl, guanyl, cyano, cyanoamino, isocyano, isocyanato,diazo, azido, hydrazino, triazano, nitrilo, isonitrilo, nitro, nitroso,isonitroso, nitrosamino, imino, nitrosimino, oxo, C₁-C₆ alkylthio,sulfamino, sulfamoyl, sulfeno, sulfhydryl, sulfinyl, sulfo, sulfonyl,sulfoxy, thiocarboxy, thiocyano, isothiocyano, thioformamido, halo,haloalkyl, chlorosyl, chloryl, perchloryl, trifluoromethyl, iodosyl,iodyl, phosphino, phosphinyl, phospho, phosphono, arsino, selanyl,diselanyl, siloxy, silyl, silylene and carbocyclic and heterocyclicmoieties. Carbocyclic moieties include alicyclic and aromaticstructures.

Examples of carbocyclic and heterocyclic moieties include, withoutlimitation, phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl,anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl,benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl,tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl,pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl,oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl,oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, trithianyl, indolizinyl, pyrazolyl, pyrazolinyl,pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl,carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

In a preferred embodiment of formula I, X is oriented meta relative toC-1, and Y is oriented ortho relative to X and para relative to C-1.More preferably, W is a bond, —(CH₂)_(n)—NH—(CH₂)_(m)— or —(CH₂)_(n)—; mis 1-3; n is 0-3; and Z is —CO₂H, —NO₂, —NH₂, —SO₃H, halo, C₅-C₆heteroaryl, carboxyphenylthio, or mono- or dicarboxyphenylsulfonyl.

Examples of this embodiment are set forth below in Table I.

TABLE I

2-[(4-carboxyphenyl)- sulfonyl]-1,4- benzenedicarboxylic acid (1)

2-[(2,5-dicarboxyphenyl)- sulfonyl]-1,4- benzenedicarboxylic acid (2)

1,2,4-benzenetricarboxylic acid (3)

2-[(2-carboxyphenyl)thio]- 1,4-benzenedicarboxylic acid (4)

2-nitro-1,4- benzenedicarboxylic acid (5)

2-bromo-1,4- benzenedicarboxylic acid (6)

2-amino-1,4- benzenedicarboxylic acid (7)

2-sulfoterephthalic acid, monosodium salt (8)

2-carboxymethyl-14- benzenedicarboxylic acid (9)

2-[(2-furanylmethyl)- amino]-1,4- benzenedicarboxylic acid (10)

2-[(carboxymethyl)amino]- 1,4-benzenedicarboxylic acid (11)

In another preferred embodiment of formula I, X is oriented orthorelative to C-1, and Y is oriented para relative to X and meta relativeto C-1.

More preferably, (1) when W is a bond, then Z is —CO₂H, —OH, —NO₂,—C(O)(NHR₅), —SR₅, —COR₅, or —NH(CH₂R₅), and R₅ is an aryl or aheteroaryl that is independently unsubstituted or substituted with oneor more alkyl, nitro or carboxy group(s); and (2) when W is —(CH₂)_(n)—and n is 1-3, then Z is —SH.

Examples of this embodiment are set forth below in Table II.

TABLE II

4-(4-nitrobenzoyl)-1,3- benzenedicarboxylic acid (12)

4-[4-(2,4-dicarboxybenzoyl)phenoxy]- 1,2-benzenedicarboxylic acid (13)

4-[[(2,4,6-trimethylphenyl)amino]- carbonyl]-1,3-benzenedicarboxylicacid (14)

4-nitro-1,3-benzenedicarboxylic acid (15)

4-[(1-naphthalenylamino)-carbonyl]-1,3- benzenedicarboxylic acid (16)

1,2,4-benzenetricarboxylic acid (17)

4-[(2-carboxyphenyl)thio]-1,3- benzenedicarboxylic acid (18)

4-[3-[[3-(2,4-dicarboxyphenoxy)propyl]-dithio]propoxy]-1,3-benzenedicarboxylic acid (19)

4-hydroxy-1,3-benzenedicarboxylic acid (20)

4-[(2-furanylmethyl)amino]-1,3- benzenedicarboxylic acid (21)

4-(2-mercaptoethyl)-1,3- benzenedicarboxylic acid (22)

In another preferred embodiment of formula I, X is oriented metarelative to C-1, and Y is oriented meta relative to X and meta relativeto C-1.

More preferably (1) when W is a bond, —(CH₂)_(n)— or —O(CH₂)_(m)— and mand n are independently 0-3, then Z is —SO₃H, —NO₂, —NH₂, —CO₂H, —OH,—PO₃H, —CO(NHOH) or —SH; (2) when W is —(CH₂)_(n)NH(CH₂)_(m)— and m andn are independently 0-3, then Z is —CO₂H or C₅-C₆ heteroaryl and (3)when W is a bond, then Z is either (a) a heteroaryl that isunsubstituted or substituted with an aryl that is unsubstituted orsubstituted with one or more C₁-C₃ alkyl, halo, nitro or hydroxygroup(s), or (b) —SO₂(NHR₆) or —NH(COR₆), wherein R₆ is an aryl that isunsubstituted or substituted with one or more nitro, amino, halo orhydroxy group(s).

Examples of this embodiment are set forth below in Table III.

TABLE III

5-[4,5-dihydro-5-(4-hydroxyphenyl)-3- phenyl-1H-pyrazol-1-yl]-1,3-benzenedicarboxylic acid (23)

5-(4,5-dihydro-3-methyl-5-phenyl-1H-pyrazol-1-yl)-1,3-benzenedicarboxylic acid (24)

5-[[(4-chloro-3- nitrophenyl)amino]sulfonyl]-1,3- benzenedicarboxylicacid (25)

5-[[[4-chloro-3-[[3-(2-methoxyphenyl)-1,3-dioxopropyl]amino]phenyl]amino]sulfonyl- 1,3-benzenedicarboxylic acid(26)

5-[[3-[4-(acetylamino)phenyl]-1,3- dioxopropyl]amino]-1,3-benzenedicarboxylic acid (27)

5-acetylamino-1,3-benzenedicarboxylic acid (28)

5-[[(1-hydroxy-2-naphthalenyl)carbonyl]-methylamino]-1,3-benzenedicarboxylic acid (29)

5-(4-carboxy-2-nitrophenoxy)-1,3- benzenedicarboxylic acid (30)

5-sulfo-1,3-benzenedicarboxylic acid (31)

5-nitro-1,3-benzenedicarboxylic acid (32)

5-amino-1,3-benzenedicarboxylic acid (33)

1,3,5-benzenetricarboxylic acid (34)

5-[[3-amino-4- chlorophenyl)amino]sulfonyl]-1,3- benzenedicarboxylicacid (35)

5-(3-mercaptopropoxy)-1,3- benzenedicarboxylic acid (36)

5-hydroxy-1,3-benzenedicarboxylic acid (37)

5-(2-mercaptoethoxy)-1,3- benzenedicarboxylic acid (38)

5-[(hydroxyamino)-carbonyl]-1,3- benzenedicarboxylic acid (39)

5-phosphono-1,3-benzenedicarboxylic acid (40)

5-mercaptomethyl-1,3- benzenedicarboxylic acid (41)

5-phosphonomethyl-1,3- benzenedicarboxylic acid (42)

5-[[(carboxymethyl)amino]-methyl]-1,3- benzenedicarboxylic acid (43)

5-[(carboxymethyl)amino]-1,3- benzenedicarboxylic acid (44)

5-[[(2-furanylmethyl)aminol-methyl]- 1,3-benzenedicarboxylic acid (45)

5-[2-(hydroxyamino)-2-oxoethyl]-1,3- benzenedicarboxylic acid (46)

5-(2-mercaptoethyl)-1,3- benzenedicarboxylic acid (47)

The compounds of formula I possess one or more asymmetric carboncenter(s) and are thus capable of existing in the form of opticalisomers as well as in the form of racemic or non-racemic mixtures ofoptical isomers. The optical isomers can be obtained by resolution ofthe racemic mixtures according to conventional processes well known inthe art, for example by formation of diastereoisomeric salts bytreatment with an optically active acid or base and then separation ofthe mixture of diastereoisomers by crystallization followed byliberation of the optically active bases from these salts. Examples ofappropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric,ditoluoyltartaric, and camphorsulfonic acid.

A different process for separating optical isomers involves the use of achiral chromatography column optimally chosen to maximize the separationof the enantiomers. Still another available method involves synthesis ofcovalent diastereoisomeric molecules, for example, esters, amides,acetals, ketals, and the like, by reacting compounds used in theinventive methods and pharmaceutical compositions with an opticallyactive acid in an activated form, an optically active diol or anoptically active isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. In some cases hydrolysis to the parentoptically active drug is not necessary prior to dosing the patient sincethe compound can behave as a prodrug. The optically active compounds ofthe present invention can likewise be obtained by utilizing opticallyactive starting materials.

It is understood that the compounds of formula I encompass individualoptical isomers as well as racemic and non-racemic mixtures.

Methods of the Invention Methods for Inhibiting NAALADase EnzymeActivity

The present invention relates to a method for inhibiting NAALADaseenzyme activity in an animal or a mammal, comprising administering tosaid animal or mammal an effective amount of a compound of formula I, asdefined above.

Methods for Treating Glutamate Abnormalitites

The present invention further relates to a method for treating aglutamate abnormality in an animal or a mammal, comprising administeringto said animal or mammal an effective amount of a compound of formula I,as defined above.

Preferred glutamate abnormalities to be treated are compulsivedisorders, stroke, demyelinating disease, schizophrenia, Parkinson'sdisease, ALS, diabetic neuropathy, pain, anxiety, anxiety disorders,glaucoma, and memory impairment. More preferably, the compulsivedisorder is alcohol, nicotine or cocaine dependence.

Stroke patients often experience a significant temporal delay betweenthe onset of ischemia and the time to initiation of therapy. Thus, thereis a need for neuroprotectants with a long therapeutic window ofopportunity. It is expected that the compounds of formula I have atherapeutic window of opportunity of at least 1 hour. Accordingly, whenthe glutamate abnormality is stroke, the compound of formula I may beadministered to said animal or mammal 60 minutes, 120 minutes, or morefollowing onset of stroke.

Without being bound to any particular mechanism of action, preferredcompounds of the present invention are expected to be those that blockglutamate release pre-synaptically without interacting withpost-synaptic glutamate receptors. Such compounds would be devoid of thebehavioral toxicities associated with post-synaptic glutamateantagonists.

Methods for Effecting a Neuronal Activity

The present invention further relates to a method for effecting aneuronal activity in an animal or a mammal, comprising administering tosaid animal or mammal an effective amount of a compound of formula I, asdefined above.

The neuronal activity that is effected by the inventive method may bestimulation of damaged neurons, promotion of neuronal regeneration,prevention of neurodegeneration, or treatment of a neurologicaldisorder.

Examples of neurological disorders that are treatable by the methods ofthe present invention include without limitation: trigeminal neuralgia;glossopharyngeal neuralgia; Bell's Palsy, myasthenia gravis; musculardystrophy, Amyotrophic Lateral Sclerosis (“ALS”); progressive muscularatrophy, progressive bulbar inherited muscular atrophy, herniated,ruptured or prolapsed invertebrate disk syndromes; cervical spondylosis;plexus disorders; thoracic outlet destruction syndromes; neuropathy,pain; Alzheimer's disease; Parkinson's disease; ALS; and Huntington'sdisease.

The inventive method is particularly useful for treating peripheralneuropathy and neuropathic pain such as peripheral neuropathy orneuropathic pain induced by HIV, chemicals (for example, toxins, lead,dapsone, vitamins, paclitaxel chemotherapy, HAART therapy), or diabetessuch as type 1 and type 2 diabetes.

The inventive method is also particularly useful for treating traumaticbrain injury, physical damage to spinal cord, stroke associated withbrain damage, demyelinating disease, and neurological disorders relatingto neurodegeneration such as Alzheimer's disease, Parkinson's disease,and ALS.

When the neurological disorder is pain, the compound of formula I ispreferably administered in combination with an effective amount ofmorphine.

Methods for Treating Prostate Diseases

The present invention further relates to a method for treating aprostate disease in an animal or a mammal, comprising administering tosaid animal or mammal an effective amount of a compound of formula I, asdefined above.

Methods for Treating Cancers

The present invention further relates to a method for treating cancer inan animal or a mammal, comprising administering to said animal or mammalan effective amount of a compound of formula I, as defined above.

Preferred cancers to be treated are those in tissues where NAALADaseresides, including without limitation the brain, kidney, and testis.

Methods for Inhibiting Angiogenesis

The present invention further relates to a method for inhibitingangiogenesis in an animal or a mammal, comprising administering to saidanimal or mammal an effective amount of a compound of formula I, asdefined above.

Angiogenesis may be necessary for fertility or metastasis of cancertumors, or may be related to an angiogenic-dependent disease. Thus, theinventive methods may also be useful for treating anangiogenic-dependent disease including, without limitation, rheumatoidarthritis, cardiovascular diseases, neovascular diseases of the eye,peripheral vascular disorders, dermatologic ulcers, and cancerous tumorgrowth, invasion, and metastasis.

Methods for Treating TGF-β Abnormalities

The present invention further relates to a method for treating a TGF-βabnormality in an animal or a mammal, comprising administering to saidanimal or mammal an effective amount of a compound of formula I, asdefined above. Preferred TGF-β abnormalities to be treated areneurodegenerative disorders, extra-cellular matrix formation disorders,cell-growth related diseases, infectious diseases, immune relateddiseases, epithelial tissue scarring, collagen vascular diseases,fibroproliferative disorders, connective tissue disorders, inflammation,inflammatory diseases, respiratory distress syndrome, and infertility.

Preferred neurodegenerative disorders to be treated are neural tissuedamage resulting from ischemia reperfusion injury, myelination, andneurodegeneration.

Preferred cell-growth related disorders to be treated are thoseaffecting kidney cells, hematopoietic cells, lymphocytes, epithelialcells, and endothelial cells.

Preferred infectious diseases to be treated are those caused by amacrophage pathogen, particularly a macrophage pathogen such asbacteria, yeast, fungi, viruses, protozoa, Trypanosoma cruzi,Histoplasma capsulatum, Candida albicans, Candida parapsilosis,Cryptococcus neoformans, Salmonella, Pneumocystis, Toxoplasma, Listeria,Mycobacteria, Rickettsia, and Leishmania. Mycobacteria include withoutlimitation Mycobacterium tuberculosis and Mycobacterium leprae.Toxoplasma includes without limitation Toxoplasma gondii. Rickettsiaincludes without limitation R. prowazekii, R. coronii, and R.tsutsugamushi.

Other preferred infectious diseases to be treated are single or multiplecutaneous lesions, mucosal disease, Chagas' disease, acquiredimmunodeficiency syndrome (“AIDS”), toxoplasmosis, leishmaniasis,trypanosomiasis, shistosomiasis, cryptosporidiosis, Mycobacterium aviuminfections, Pneumocystis carinii pneumonia, and leprosy.

Preferred immune related diseases to be treated are autoimmunedisorders; impaired immune function; and immunosuppression associatedwith an infectious disease, particularly, trypanosomal infection, viralinfection, human immunosuppression virus, human T cell lymphotropicvirus (“HTLV-1”), lymphocytic choriomeningitis virus, or hepatitis.

Preferred collagen vascular diseases to be treated include progressivesystemic sclerosis (“PSS”), polymyositis, scleroderma, dermatomyositis,eosinophilic fascitis, morphea, Raynaud's syndrome, interstitialpulmonary fibrosis, scleroderma, and systemic lupus erythematosus.

Preferred fibroproliferative disorders to be treated include diabeticnephropathy, kidney disease, proliferative vitreoretinopathy, livercirrhosis, biliary fibrosis, and myelofibrosis. Especially preferredkidney diseases include mesangial proliferative glomerulonephritis,crescentic glomerulonephritis, diabetic neuropathy, renal interstitialfibrosis, renal fibrosis in transplant patients receiving cyclosporin,and HIV-associated nephropathy.

Preferred connective tissue disorders to be treated include scleroderma,myelofibrosis, and hepatic, intraocular and pulmonary fibrosis.

Preferred inflammatory diseases to be treated are associated with PSS,polymyositis, scleroderma, dermatomyositis, eosinophilic fascitis,morphea, Raynaud's syndrome, interstitial pulmonary fibrosis,scleroderma, systemic lupus erythematosus, diabetic nephropathy, kidneydisease, proliferative vitreoretinopathy, liver cirrhosis, biliaryfibrosis, myelofibrosis, mesangial proliferative glomerulonephritis,crescentic glomerulonephritis, diabetic neuropathy, renal interstitialfibrosis, renal fibrosis in transplant patients receiving cyclosporin,or HIV-associated nephropathy.

Without being limited to any particular mechanism of action, preferredcompounds of the present invention treat inflammatory diseases byregulating TGF-β and/or inhibiting myeloperoxidase.

Other uses associated with the compounds' TGF-β regulating propertiesinclude:

-   -   stimulating growth of tissue, glands or organs, particularly        growth that would enhance milk production or weight gain;    -   stimulating cell proliferation, particularly proliferation of        fibroblasts, mesenchyrnal cells, or epithelial cells;    -   inhibiting cell growth, particularly of epithelial cells,        endothelial cells, T and B lymphocytes, and thymocytes;    -   inhibiting expression of adipose, skeletal muscle and        hematopoietic phenotypes, neoplasms, non-cytocidal viral or        other pathogenic infections and autoimmune disorders;    -   mediating disease resistance and susceptibility;    -   suppressing cellular immune response;    -   inhibiting scar tissue formation, preferably in skin or other        epithelial tissue that has been damaged by wounds resulting from        accidental injury, surgical operations, trauma-induced        lacerations or other trauma, or wounds involving the peritoneum        for which the excessive connective tissue formation is abdominal        adhesions;    -   increasing the effectiveness of a vaccine, particularly a        vaccine for an allergy towards, e.g., dust or hayfever; and    -   inhibiting polyp formation.

Diagnostic Methods and Kits

The compounds of the present invention are useful for in vitro and invivo diagnostic methods for detecting diseases, disorders and conditionswhere NAALADase levels are altered including, without limitation,neurological disorders, glutamate abnormalities, neuropathy, pain,compulsive disorders, prostate diseases, cancers and TGF-βabnormalities.

Accordingly, the present invention also relates to a method fordetecting a disease, disorder or condition where NAALADase levels arealtered, comprising:

-   -   (i) contacting a sample of bodily tissue or fluid with a        compound of the invention, as defined above, wherein said        compound binds to any NAALADase in said sample; and    -   (ii) measuring the amount of any NAALADase bound to said sample,        wherein the amount of NAALADase is diagnostic for said disease,        disorder or condition.

The present invention further relates to a method for detecting adisease, disorder or condition where NAALADase levels are altered in ananimal or a mammal, comprising:

-   -   (i) labeling a compound of the invention, as defined above, with        an imaging reagent;    -   (ii) administering to said animal or mammal an effective amount        of the labeled compound;    -   (iii) allowing said labeled compound to localize and bind to        NAALADase present in said animal or mammal; and    -   (iv) measuring the amount of NAALADase bound to said labeled        compound, wherein the amount of NAALADase is diagnostic for said        disease, disorder or condition.

The present invention further relates to a diagnostic kit for detectinga disease, disorder or condition where NAALADase levels are altered,comprising a compound of the invention, as defined above, labeled with amarker. The kit may further comprise buffering agents, agents forreducing background interference, control reagents and/or apparatus forconducting the test.

Examples of bodily tissues and fluids include, without limitation,prostate tissue, ejaculate, seminal vesicle fluid, prostatic fluid,urine, blood, saliva, tears, sweat, lymph and sputum.

The compound may be labeled with a marker using techniques known in theart. Useful markers include, without limitation, enzymatic markers andimaging reagents. Examples of imaging reagents include radiolabels suchas ¹³¹I, ¹¹¹In, ¹²³I, ⁹⁹Tc, ³²P, ¹²⁵I, ³H and ¹⁴C; fluorescent labelssuch as fluorescein and rhodamine; and chemiluminescers such asluciferin.

The amount of NAALADase can be measured using techniques known in theart including, without limitation, assays (such as immunometric,calorimetric, densitometric, spectrographic and chromatographic assays)and imaging techniques (such as magnetic resonance spectroscopy (MRS),magnetic resonance imaging (MRI), single-photon emission computedtomography (SPECT) and positron emission tomography (PET)).

The amount of NAALADase can be measured in vivo using known imagingtechniques, as described above.

Incorporation by Reference

The relationship between NAALADase inhibitors and glutamate, and theeffectiveness of NAALADase inhibitors in treating and detecting variousdiseases, disorders and conditions have been discussed in U.S. Pat. Nos.5,672,592; 5,795,877; 5,804,602; 5,824,662; 5,863,536; 5,977,090;5,981,209; 6,011,021; 6,017,903; 6,025,344; 6,025,345; 6,046,180; and6,228,888; allowed U.S. patent application Ser. No. 09/228,391, forwhich the issue fee has been paid; International Publication Nos. WO00/01668 and WO 00/38785; a U.S. Provisional Application filed on Jan.17, 2001; and other references generally known in the art. The presentinventors hereby incorporate by reference, as though set forth herein infull, the entire contents of the aforementioned patents, patentapplications, and publications, particularly their discussions, figuresand data regarding the effectiveness of NAALADase inhibitors ininhibiting angiogenesis, in effecting TGF-β activity, in diagnosingdiseases, and in treating ischemia, spinal cord injury, demyelinatingdiseases, Parkinson's disease, ALS, alcohol dependence, nicotinedependence, cocaine dependence, prostate disease, cancer, diabeticneuropathy, pain, schizophrenia, anxiety, anxiety disorder, and memoryimpairment. The present inventors have discovered that the inventivecompounds are effective NAALADase inhibitors. Thus, the inventivecompounds are expected to have the same uses as the NAALADase inhibitorsdisclosed in the patents, patent applications, and publications that areincorporated by reference.

Pharmaceutical Compositions of the Present Invention

The present invention also relates to a pharmaceutical compositioncomprising:

-   -   (i) an effective amount of a compound of formula I; and    -   (ii) a pharmaceutically acceptable carrier.

Preferred compounds of formula I are set forth above.

Preferably, the compound of formula I is present in an effective amountfor inhibiting NAALADase enzyme activity, treating glutamateabnormalities, effecting neuronal activity, treating diabeticneuropathy, pain, prostate diseases, and cancers, inhibitingangiogenesis, and treating TGF-β abnormalities, compulsive disorders,and glaucoma.

Route of Administration

In the inventive methods, the compounds will generally be administeredto a patient in the form of a pharmaceutical formulation. Suchformulation preferably includes, in addition to the active agent, aphysiologically acceptable carrier and/or diluent. The compounds may beadministered by any means known to an ordinarily skilled artisan. Forexample, the compounds may be administered orally, parenterally, byinhalation spray, topically, rectally, nasally, buccally, vaginally, orvia an implanted reservoir in dosage formulations containingconventional non-toxic pharmaceutically acceptable carriers, adjuvants,and vehicles. The term “parenteral” as used herein includessubcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal,intraventricular, intrasternal, intracranial, or intraosseous injectionand infusion techniques. The exact administration protocol will varydepending upon various factors including the age, body weight, generalhealth, sex and diet of the patient; the determination of specificadministration procedures would be routine to an ordinarily skilledartisan.

To be effective therapeutically as central nervous system targets, thecompounds should readily penetrate the blood-brain barrier whenperipherally administered. Compounds that cannot penetrate theblood-brain barrier can be effectively administered by anintraventricular route or by other methods recognized in the art. See,e.g., U.S. Pat. Nos. 5,846,565; 5,651,986; and 5,626,862.

Dosage

The compounds and compositions of the present invention may beadministered by a single dose, multiple discrete doses, or continuousinfusion. The compounds are well suited to continuous infusion. Pumpmeans, particularly subcutaneous pump means, are preferred forcontinuous infusion.

Dose levels on the order of about 0.001 to about 10,000 mg/kg of theactive ingredient compound are useful in the treatment of the aboveconditions, with preferred levels being about 0.1 to about 1,000 mg/kg,and more preferred levels being about 1 to about 100 mg/kg. The specificdose level for any particular patient will vary depending upon a varietyof factors, including the activity and the possible toxicity of thespecific compound employed; the age, body weight, general health, sex,and diet of the patient; the time of administration; the rate ofexcretion; drug combination; the severity of the particular diseasebeing treated; and the form of administration. Typically, in vitrodosage-effect results provide useful guidance on the proper doses forpatient administration. Studies in animal models are also helpful. Theconsiderations for determining the proper dose levels are well known inthe art.

Administration Regimen

For the methods of the present invention, any administration regimenwell known to an ordinarily skilled artisan for regulating the timingand sequence of drug delivery can be used and repeated as necessary toeffect treatment. Such regimen may include pretreatment and/orco-administration with additional therapeutic agents.

Co-Administration with Other Treatments

The compounds and compositions of the present invention may be usedalone or in combination with one or more additional agent(s) forsimultaneous, separate, or sequential use.

The additional agent(s) may be any therapeutic agent(s) known to anordinarily skilled artisan, including without limitation: one or morecompound(s) of formula I; steroids, for example, hydrocortisomes such asmethylprednisolone; anti-inflammatory or anti-immune drugs, such asmethotrexate, azathioprine, cyclophosphamide or cyclosporin A;interferon-β; antibodies, such as anti-CD4 antibodies; agents which canreduce the risk of a second ischemic event, such as ticlopidine;chemotherapeutic agents; immunotherapeutic compositions; electromagneticradiosensitizers; and morphine.

The compounds of the present invention can be co-administered with oneor more therapeutic agents either (i) together in a single formulation,or (ii) separately in individual formulations designed for optimalrelease rates of their respective active agent. Each formulation maycontain from about 0.01% to about 99.99% by weight, preferably fromabout 3.5% to about 60% by weight, of a compound of the presentinvention, as well as one or more pharmaceutical excipients, such aswetting, emulsifying, and pH buffering agents.

Preparation of Compounds

The compounds of the present invention can be readily prepared bystandard techniques of organic chemistry, utilizing the generalsynthetic pathways depicted below in Schemes I, II, and III. Precursorcompounds may be purchased from commercial sources or prepared bymethods known in the art.

EXAMPLES

The following examples are illustrative of the present invention and arenot intended to be limitations thereon. Unless otherwise indicated, allpercentages are based upon 100% by weight of the final composition.

Example 1 Preparation of 5-phosphonomethyl-1,3-benzenedicarboxylic acid(Scheme I, Compound 40)

Preparation of diethyl5-[(diethoxyphosphinyl)methyl]-1,3-benzenedicarboxylate

A solution of 5-bromomethyl-1,3-benzenedicarboxylate (Collman et al., J.Am. Chem. Soc., 116(14) (1994) 6245-6251; 0.315 g, 1.0 mmol) intriethylphosphite (3.0 mL) was heated at 15° C. for 5 hours. The solventwas removed under reduced pressure and the residual oil was purified bychromatography to give 0.248 g of colorless oil (67% yield).

¹H NMR: (CDCl₃) δ 1.28 (t, 3H), 1.42 (t, 3H), 3.26 (d, 2H), 4.06 (q,2H), 4.41 (q, 2H), 8.17 (s, 2H), 8.58 (s, 1H).

TLC: R_(f) 0.10 (EtOAc/Hexanes 1/1).

Preparation of 5-phosphonomethyl-1,3-benzenedicarboxylic acid (40)

A solution of diethyl5-[(diethoxyphosphinyl)methyl]-1,3-benzenedicarboxylate (0.186 g, 0.5mmol) in 12 N HCl (2.5 mL) was heated at 100° C. for 24 hours. Theresulting precipitate was washed with water and dried under vacuum togive 0.057 g of white powder (41% yield).

¹H NMR: (D₂O) δ 3.11 (d, 2H), 7.93 (s, 2H), 8.19 (s, 1H).

TLC: R_(f) 0.20 (EtOAc/Hexanes 1/1).

Elemental Analysis: Calculated for C₉H₇O₇P.H₂O: C, 38.86; H, 3.99.Found: C, 38.74; H, 4.08.

Example 2 Preparation of5-[(hydroxyamino)carbonyl]-1,3-benzene-dicarboxylic acid (Scheme II,Compound 39)

Preparation of diethyl5-[[(phenylmethoxy)amino]carbonyl]-1,3-benzenedicarboxylate

To a solution of diethyl 1,3,5-benzenetricarboxylate (3.192 g, 20 mol)and O-benzylhydroxyamine hydrochloride (4.789 g, 19 mmol) in 40 mL wereadded N-methylmorpholine (2.2 mL, 20 mmol) and EDC (3.834 g, 20 mmol) at0° C., and the mixture was stirred at room temperature for 20 hours. Thesolvent was removed by evaporator and the residue was dissolved in EtOAc(150 mL). The organic solution was washed with 1 N HCL (150 mL), washedwith saturated aqueous NaHCO₃ (50 mL), dried over Na₂SO₄, andconcentrated to give white solid. This material was recrystallized fromEtOAc to give 4.154 g of white powder (59% yield).

¹H NMR: (CDCl₃) δ 1.41 (t, 6H), 4.40 (q, 4H), 5.05 (s, 2H), 7.3-7.5 (m,5H), 8.52 (s, 2H), 8.76 (s, 1H), 9.1 (br, 1H).

TLC: R_(f) 0.62 (EtOAc/Hexanes 1/1).

Preparation of diethyl5-[(hydroxyamino)carbonyl]-1,3-benzenedicarboxylate

To a solution of diethyl5-[[(phenylmethoxy)amino]-carbonyl]-1,3-benzenedicarboxylate (0.742 g,2.0 mmol) in ethanol (10 mL) was added a suspension of Pd/C in ethanol(5 mL), and the mixture was shaken under hydrogen (50 psi) for 20 hours.The catalyst was removed by filtration through a pad of celite and thefiltrate was concentrated to give white powder. This material was washedwith ethanol (10 mL×2) and dried under vacuum to give 0.380 g of whitepowder (67% yield).

¹H NMR: (CD₃OD) δ 1.44 (t, 6H), 4.45 (q, 4H), 8.60 (s, 2H), 8.72 (s,1H).

TLC: R_(f) 0.20 (EtOAc/Hexanes 1/1).

Preparation of 5-[)hydroxyamino)carbonyl]-1,3-benzene-dicarboxylic acid(39)

To a solution of diethyl5-[(hydroxyamino)carbonyl]-1,3-benzenedicarboxylate (0.281 g, 1.0 mmol)in acetone (5 mL) was added 1.0 N NaOH (5 mL) at room temperature, andthe mixture was stirred at room temperature for 2 hours. The solvent wasremoved under reduced pressure and the residue was taken up with 1 N HCl(15 mL) to give white precipitate. This material was dried under vacuumto give 0.096 g of white solid (43% yield).

¹H NMR: (D₂O) δ 8.52 (s, 2H), 8.76 (s, 1H).

Elemental Analysis: Calculated for C₉H₇NO₆.H₂O: C, 44.45; H, 3.73; N,5.76. Found: C, 44.47; H, 3.78; N, 5.74.

Example 3 Preparation of 4-(2-mercaptoethyl)-1,3-benzenedicarboxylicacid (Scheme III, Compound 22)

Preparation of dimethyl4-trifluoromethanesulfonyloxy-1,3-benzenedicarboxylate

To a solution of dimethyl 4-hydroxy-isophthalate (0.850 g, 4.04 mmol) inCH₂Cl₂ (15 mL) were added triethylamine (0.6 mL, 4.3 mmol) and triflicanhydride (0.8 mL, 4.76 mmol) at 0° C., and the mixture was stirred at0° C. for 18 hours. The solvent was evaporated and the residue wasdiluted with ether (30 mL). The organic solution was washed with 1 N HCl(30 mL×3), dried over MgSO₄, and concentrated to give 1.30 g of darkyellow oil (93% yield).

¹H NMR: (CDCl₃) δ 3.97 (s, 3H), 4.00 (s, 3H), 7.4 (d, 1H), 8.3 (d, 1H),8.74 (s, 1H).

Preparation of dimethyl 4-ethenyl-1,3-benzenedicarboxylate

To a solution of dimethyl4-trifluoromethanesulfonyl-oxy-1,3-benzenedicarboxylate (1.5 g, 4.38mmol) in dioxane (50 mL) were added Pd(PPh₃)₄ (510 mg, 0.44 mmol),lithium chloride (1.3 g, 30.7 mmol) and tributyl(vinyl)tin (1.5 mL, 5.13mmol) at room temperature. The mixture was heated at 100° C. for 5hours. The reaction mixture was filtered and the filtrate wasconcentrated and passed through a column of silica gel(Hexanes/EtOAc=10:1) to give 1.1 g of colorless oil (84% yield).

¹H NMR: (CDCl₃) δ 3.92 (s, 3H), 3.93 (s, 3H), 5.45 (d, 1H), 5.73 (d,1H), 7.49 (m, 1H), 7.66 (d, 1H), 8.13 (d, 1H), 8.53 (s, 1H).

Preparation of dimethyl 4-[2-(acetylthio)ethyl]-1,3-benzenedicarboxylate

To a degassed solution of dimethyl 4-ethenyl-1,3-benzenedicarboxylate(415 mg, 1.88 mmol) in benzene (6 mL) were added AIBN (33 mg, 0.21 mmol)and thioacetic acid (0.27 mL, 3.78 mmol), and the mixture was refluxedfor 5 hours. The reaction mixture was diluted with aqueous NaHCO₃solution (15 mL) and extracted with EtOAc (15 mL). The organic layer wasdried over MgSO₄ and concentrated. The residual material was purified bysilica gel chromatography (hexanes/EtOAc=10:1) to give 0.150 g ofcolorless oil (27% yield).

¹H NMR: (CDCl₃) δ 2.32 (s, 3H), 3.16 (t, 2H), 3.28 (t, 2H), 3.94 (s,6H), 7.42 (d, 1H), 8.09 (d, 1H), 8.58 (s, 1H).

Preparation of 4-(2-mercaptoethyl)-1,3-benzenedicarboxylic acid (22)

To a degassed solution of dimethyl4-[2-(acetylthio)ethyl]-1,3-benzenedicarboxylate (0.130 g, 0.44 mmol) inTHF (5 mL) was added a degassed solution of 5 N NaOH (5 mL). Thereaction mixture was stirred under nitrogen overnight. The reactionmixture was diluted with H₂O (10 mL) and extracted with EtOAC (10 mL).The organic layer was dried over MgSO₄ and concentrated to give 0.045 gof white solid (45% yield).

¹H NMR: (DMSO) δ 2.67 (t, 2H), 3.21 (t, 2H), 7.37 (d, 1H), 7.98 (d, 1H),8.46 (s, 1H)

¹³C NMR: (DMSO) δ 26.64, 40.60, 130.87, 132.05, 133.46, 133.81, 134.13,148.53, 169.22, 170.20

Elemental Analysis: Calculated for C₁₀H₁₀SO₄.0.3 EtOAc: C, 53.24; H,4.95; S, 12.69. Found: C, 53.37; H, 4.87; S, 12.84.

MS(FAB): 225

Example 4

In Vitro Inhibition of NAALADase Activity

Various compounds of formula I were tested for in vitro inhibition ofNAALADase activity, and the results are provided below in Table IV.

TABLE IV Compound K_(i) (nM) 4-[4-(2,4-dicarboxybenzoyl)phenoxy]-1,2-1170 benzenedicarboxylic acid (13)2-[(4-carboxyphenyl)sulfonyl]-1,4-benzenedicarboxylic 2370 acid (1)2-[(2,5-dicarboxyphenyl)sulfonyl]-1,4- 1870 benzenedicarboxylic acid (2)4-[(2-carboxyphenyl)thio]-1,3-benzenedicarboxylic acid 3980 (18)2-[(2-carboxyphenyl)thio]-1,4-benzenedicarboxylic acid 572 (4)4-[3-[[3-(2,4-dicarboxyphenoxy)-propyl]-dithio]propoxy]- 37501,3-benzenedicarboxylic acid (19)5-(3-mercaptopropoxy)-1,3-benzenedicarboxylic acid (36) 33005-(2-mercaptoethoxy)-1,3-benzenedicarboxylic acid (38) 145005-[(hydroxyamino)-carbonyl]-1,3-benzenedicarboxylic 1000 acid (39)5-phosphono-1,3-benzenedicarboxylic acid (40) 140005-mercaptomethyl-1,3-benzenedicarboxylic acid (41) 65005-phosphonomethyl-1,3-benzenedicarboxylic acid (42) 31005-[(carboxymethyl)amino]-1,3-benzenedicarboxylic acid 100000 (44)5-[[(2-furanylmethyl)amino]methyl]-1,3- 50000 benzenedicarboxylic acid(45) 2-carboxymethyl-1,4-benzenedicarboxylic acid (9) 90005-[2-(hydroxyamino)-2-oxoethyl]-1,3- 12000 benzenedicarboxylic acid (46)4-(2-mercaptoethyl)-1,3-benzenedicarboxylic acid (22) 1165-(2-mercaptoethyl)-1,3-benzenedicarboxylic acid (47) 5100Protocol for Assaying In Vitro Inhibition of NAALADase Activity

The following were combined in each assay tube: 100 μof 10 mM CoCl₂, 250μL of 200 mM Tris chloride, 100 μL tissue, 100 μL of 10 mM NAALADaseinhibitor in Bakers H₂O, and Bakers H₂O to make a total volume of 950μL. Each tube was then incubated for 10 minutes in a 37° C. water bath.50 μL of 3-H-NAAG was then added to each assay tube and incubated for anadditional 15 minutes in a 37° C. water bath. The assay was stopped byadding 1.0 ml of 0.1 M sodium phosphate.

Glutamate released by the action of the NAALADase enzyme was separatedfrom the assay solution using an anion exchange resin. The resin wasequilibrated to 25° C., 2.0 ml of the resin was added to a Pasteurpipette pre-loaded with a single glass bead, and each column was washedtwice with distilled H₂O. A column was placed over a scintillation vialand 200 μL of an assay sample was loaded onto the column. Afterdraining, glutamate was eluted using two 1.0 ml washes of 1 M formicacid. After addition of 10 ml of scintillation cocktail, each sample wascounted for 2 minutes on a scintillation counter.

Example 5

In Vitro Assay on Ischemia

To examine the in vitro effect of the compounds of formula I onischemia, cortical cell cultures were treated with various compounds offormula I during an ischemic insult utilizing potassium cyanide and2-deoxyglucose, and for one hour thereafter (for experimental details,see Vomov et al., J. Neurochem., Vol. 65, No. 4, pp. 1681-1691 (1995)).The results are provided below in Table V. Neuroprotective effect isexpressed as EC₅₀, the concentration of the compound, which is requiredto cause a 50% reduction in glutamate toxicity following an ischemicinsult.

TABLE V Compound EC₅₀ (nM)4-[3-[[3-(2,4-dicarboxyphenoxy)-propyl]dithio]propoxy]- 24901,3-benzenedicarboxylic acid (19)5-(3-mercaptopropoxy)-1,3-benzenedicarboxylic acid (36) 12405-[(hydroxyamino)-carbonyl]-1,3-benzenedicarboxylic 473 acid (39)5-mercaptomethyl-1,3-benzenedicarboxylic acid (41) 1724-(2-mercaptoethyl)-1,3-benzenedicarboxylic acid (22) 60

Example 6

Effect of NAALADase Inhibition on TGF-β in In Vitro Ischemia Model

A NAALADase inhibitor, Compound C, was added to ischemia cell culturesto determine its effect on TGF-β levels during stroke. The experimentaldata, set forth

in FIGS. 1 and 2, show increased concentrations of TGF-β1 (FIG. 1) andTGF-β2 (FIG. 2) in ischemic cell cultures treated with Compound C. Theresults indicate that NAALADase inhibition promotes the release ofendogenous TGF-β's from glial cells, which in turn providesneuroprotection for neighboring neurons.

TGF-β neutralizing antibodies were then added to the ischemic cellcultures. FIG. 3 shows that the TGF-β neutralizing antibodies blockedthe neuroprotective effect of Compound C in the in vitro ischemia model.By contrast, FIG. 4 shows that the addition of another growth factorantibody, FGF antibody, did not block the neuroprotective effect ofCompound C. The results indicate that NAALADase inhibition specificallyaffects TGF-β levels during stroke.

Example 7

Effect of NAALADase Inhibition on TGF-β in In Vivo Ischemia Model

The effect of TGF-β neutralizing antibodies on the neuroprotectiveeffect of Compound C was also studied in rats following MCAO. FIG. 6shows that treatment of MCAO rats with Compound C caused a significantrise in TGF-β1 levels during both occlusion and reperfusion, as assessedby microdialysis. The results indicate that NAALADase inhibitionprovides neuroprotection, at least in part, by regulating endogenousTGF-β's.

Additionally, FIG. 5 shows that TGF-β neutralizing antibodiessignificantly attenuated the neuroprotective effect of Compound C invivo. One of ordinary skill in the art can appreciate that theregulation of TGF-β's by NAALADase inhibitors may have implications notonly in stroke, but also in other diseases, disorders and conditionsincluding, without limitation, neurological diseases, psychiatricdiseases, demyelinating diseases, prostate cancer, inflammation, andangiogenesis.

Example 8

In Vivo Assay of NAALADase Inhibitors on Neuropathic Pain

Male Sprague-Dawley rats (200-225 g) were rendered diabetic byintravenous administration of streptozotocin (“STZ”, 70 mg/kg inphosphate buffered saline). Diabetic animals were divided into fivegroups: one group receiving Compound A (10 mg/kg or 1 mg/kg), Compound D(10 mg/kg or 1 mg/kg) or vehicle. Another group of animals (non-STZtreated) served as non-diabetic controls. Drug/vehicle treatment wasstarted in diabetic animals 45 days post-STZ administration. STZ-induceddiabetic rats were tested for sensitivity to a heat source as soon asblood glucose levels rose to 320 mg/dl or above (30 days post STZ). Therats were then acclimated to the Hargreaves apparatus and thermalnociception was monitored using an infrared heat source directed intothe dorsal surface of the hindpaw, and the time taken for the animal toremove its paw noted to the nearest 0.1 seconds (for detailed method,see Hargreaves et al., J. Biol. Chem. (1988) 263(36):19392-7). Theintensity of the beam source was adjusted such that the mean latency forcontrol animals (non-STZ treated) was approximately 10 seconds. Eachanimal was tested 8 times and the mean difference score (between meannon-diabetic control latency and mean diabetic latency) are graphicallypresented in FIGS. 13A and 13B. Diabetic rats displayed a hyperalgesia(shorter response latency) compared to non-diabetic controls, starting30 days post STZ treatment and progressively worsening in vehicletreated rats. This hyperalgesic response was completely reversed indiabetic rats receiving treatment with Compound D or A (10 mg/kg i.p.daily). Thus, the results show that NAALADase inhibition attenuatesneuropathic pain.

Example 9

In Vivo Assay of NAALADase Inhibitors on Neuropathic Pain ProgressionCCI Model

Sciatic nerve ligation, consisting of 4 ligatures tied loosely aroundthe sciatic nerve at 1 mm intervals proximal to the nerve trifurcation,was performed on rats. Following sciatic nerve ligation, the ratsexhibited a thermal hyperalgesia and allodynia. The rats were habituatedto a Hargreaves apparatus. An infrared heat source was directed onto thedorsal surface of each rat's hindpaws and the time taken for the rat towithdraw its paws was noted. The difference in scores between thelatency of the response for the paw on the operated side versus the pawon the unoperated control side was determined.

Compound C

Animals received Compound C (50 mg/kg i.p. daily) or vehicle, starting10 days post surgery. Treatment with Compound C dramatically normalizedthe difference scores between the two paws compared to the continuedhyperalgesic vehicle-treated controls. Normal (unoperated) rats hadapproximately equal latencies for both paws. This effect was significantstarting at 11 days of drug treatment and persisted through to the endof the study (for 21 days of daily dosing). The difference scores aregraphically presented in FIG. 14. The results show that NAALADaseinhibition attenuates CCI-associated hyperalgesia

Compounds D and A

Male BB/W rats (BRI, Mass) spontaneously develop a cell mediatedautoimmune destruction of pancreatic B cells, resulting in onset ofinsulin-dependent (Type I) diabetes (Awata and Guberski et al.,Endocrinology 1995 December; 136(12):5731-5). These rats have beencharacterized and shown to demonstrate neuropathies with accompanyingneural deficits such as fiber loss and degeneration, changes which arecorrelative with those seen in peripheral nerve of human diabeticpatients (Yagihasi, J. Peripher. Nerv. Syst. 1997; 2(2):113-32). Thisrenders them valuable for experimental trials of new compounds forfuture treatments of this major disorder. In the present study, CompoundD and Compound A were examined for their ability to alter theprogression of diabetic neuropathy. The rats received daily injection ofCompound D or Compound A (10 mg/kg i.p.) or vehicle, starting at theonset of diabetes (hyperglycemia) and up to 6 months thereafter. Anothergroup of non-diabetic rats also receiving vehicle were tested. Allanimals were continuously monitored for body weight, urine volume, bloodsugar and glycated haemoglobin. In the first month of the study, allanimals were tested for thermal nociception in a Hargreaves apparatus,weekly. After the first month this was done biweekly and then monthly.The testing consists of directing an infrared heat source onto thedorsal surface of the rat hindpaw and noting the time taken for theanimal to remove its paw (for detailed method, see Hargreaves et al., J.Biol. Chem. 1988 Dec. 25; 263(36):19392-7). Each animal was tested 8times and the mean withdrawal latency noted.

The results are graphically presented in FIG. 17. The results show thatdiabetic rats displayed a hyperalgesia (shorter response latency)compared to non-diabetic controls. Diabetic drug-treated rats (bothCompound D and Compound A) displayed longer withdrawal latencies thandiabetic vehicle-treated rats, starting after 4 weeks of treatment andpersisting through the six months of treatment.

Nerve conduction velocity was also measured every two weeks through thefirst eight weeks of treatment and every month thereafter through to thesix months of treatment. For detailed method, see De Koning et al.,Peptides 1987 May-Jun.; 8(3):415-22. The results are graphicallypresented in FIG. 18. Diabetic animals generally showed a reduction innerve conduction velocity compared to non-diabetic controls. However,diabetic animals receiving daily injections of NAALADase inhibitor(either Compound D or Compound A at a dose of 10 mg/kg) showedsignificantly less severe nerve conduction deficits than did thediabetic controls receiving vehicle treatment. This was apparentstarting at 8 weeks of treatment and persisted to a similar degreethrough to the six month termination point of the study. Diabeticvehicles, on the other hand, showed a progressive deterioration in nerveconduction velocity from 6 to 16 weeks after start of vehicleadministration which was maintained through to six months.

Example 10

In Vivo Assay of NAALADase Inhibitors on Diabetic Neuropathy

Motor and sensory nerve conduction velocity was also measured inSTZ-diabetic animals after 4, 8 and 12 weeks of treatment. For detailedmethod, see De Koning et al., Peptides 1987 May-Jun. 1987; 8(3):415-22.Briefly, stimulating needle electrodes were inserted close to thesciatic and tibial nerves with recording electrodes being placedsubcutaneously over the distal foot muscles, in anesthetized rats. Theresults are graphically presented in FIGS. 15A, 15B, 16A and 16B.Diabetic animals receiving vehicle showed a significant reduction inboth motor and sensory nerve conduction compared to non-diabeticanimals. Treatment with 10 mg/kg of Compound A daily for 4, 8 and 12weeks all tended to improve (increase) both motor and sensory nerveconduction velocities, with a significant improvement being observedafter 12 weeks and 8 weeks for motor and sensory nerve conductionvelocity, respectively (FIGS. 15A and 15B). A lower dose of Compound Atested (1 mg/kg) had similar effects. Treatment of animals with CompoundD at either dose also increased both motor and sensory nerve conductionvelocities above that of diabetic controls, significantly so after 12weeks of treatment for the 10 mg/kg treatment group (FIGS. 16A and 16B)and at the earlier time periods after treatment with the 1 mg/kg dose.Thus, the results show that NAALADase inhibition alters the progressionof diabetic neuropathy.

Example 11

A patient is suffering from any disease, disorder or condition mediatedby NAALADase enzyme activity, including any of the diseases, disordersor conditions described above. The patient may then be administered aneffective amount of a compound of formula I. It is expected that aftersuch treatment, the patient would not suffer any significant injury dueto, would be protected from further injury due to, or would recover fromthe disease, disorder or condition.

All publications, patents and patent applications identified above areherein incorporated by reference, as though set forth herein in full.

Those skilled in the art will recognize that the invention may be variedin many ways without departing from the invention's spirit and scope.Such variations are included within the scope of the following claims.

1. A compound of formula I

or a pharmaceutically acceptable equivalent, wherein: X is—NR—(CR₃R₄)_(m)-heteroaryl or

wherein X is oriented meta or para to C-1; m is 1-3; R₃, R₄, and R₅ areindependently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl,heteroaryl, carbocycle, heterocycle, halo, hydroxy, sulfhydryl, nitro,amino or C₁-C₆ alkoxy, wherein said alkyl, alkenyl, alkynyl, aryl,heteroaryl, carbocycle, heterocycle, or alkoxy is independentlyunsubstituted or substituted with one or more substituent(s); and Y is—COOH oriented meta or para relative to C-1.
 2. The compound of claim 1,wherein: X is oriented meta relative to C-1; and Y is oriented orthorelative to X and para relative to C-1.
 3. The compound of claim 2,wherein the compound is 2-[(2-furanylmethyl)-amino]-1,4-benzenedicarboxylic acid (10) or apharmaceutically acceptable equivalent.
 4. The compound of claim 1,wherein: X is oriented ortho relative to C-1; and Y is oriented pararelative to X and meta relative to C-1.
 5. The compound of claim 4,wherein the compound is:4-[(2-furanylmethyl)amino]-1,3-benzenedicarboxylic acid (21) or apharmaceutically acceptable equivalent.
 6. The compound of claim 1,wherein: X is oriented meta relative to C-1; and Y is oriented metarelative to X and meta relative to C-1.
 7. The compound of claim 6,wherein the compound is:5-[4,5-dihydro-5-(4-hydroxyphenyl)-3-phenyl-1H-pyrazol-1-yl]-1,3-benzenedicarboxylicacid (23);5-(4,5dihydro-3methyl-5-phenyl-1H-pyrazol-1-yl)-1,3-benzenedicarboxylicacid (24); or a pharmaceutically acceptable equivalent.
 8. Apharmaceutical composition comprising: (i) an effective amount of acompound of formula I

 or a pharmaceutically acceptable equivalent, wherein: X is—NH—(CR₃R₄)_(m)-heteroaryl or

wherein X is oriented meta or para to C-1; m is 1-3; R₃, R₄, and R₅ areindependently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl,heteroaryl, carbocycle, heterocycle, halo, hydroxy, sulfhydryl, nitro,amino or C₁-C₆ alkoxy, wherein said alkyl, alkenyl, alkynyl, aryl,heteroaryl, carbocycle, heterocycle, or alkoxy is independentlyunsubstituted or substituted with one or more substituent(s); and Y is—COOH oriented meta or para relative to C-1; and (ii) a pharmaceuticallyacceptable carrier.
 9. The composition of claim 8, wherein: X isoriented meta relative to C-1; and Y is oriented ortho relative to X andpara relative to C-1.
 10. The composition of claim 9, wherein thecompound of formula I is selected from the group consisting of:2-[(4-carboxyphenyl)sulfonyl]-1,4-benzene-dicarboxylic acid (1);2-[(2,5-dicarboxyphenyl)sulfonyl]-1,4-benzene-dicarboxylic acid (2);1,2,4-benzenetricarboxylic acid (3);2-[(2-carboxyphenyl)thio]-1,4-benzenedicarboxylic acid (4);2-nitro-1,4-benzenedicarboxylic acid (5);2-bromo-1,4-benzenedicarboxylic acid (6);2-amino-1,4-benzenedicarboxylic acid (7); 2-sulfoterephthalic acid,monosodium salt (8); 2-carboxymethyl-1,4-benzenedicarboxylic acid (9);2-[(2-furanylmethyl)-amino]-1,4-benzenedicarboxylic acid (10);2-[(carboxymethyl)amino]- 1,4-benzenedicarboxylic acid (11); andpharmaceutically acceptable equivalents.
 11. The composition of claim 8,wherein: X is oriented ortho relative to C-1; and Y is oriented pararelative to X and meta relative to C-1.
 12. The composition of claim 11,wherein the compound of formula I is4-[(2-furanylmethyl)amino]-1,3-benzenedicarboxylic acid (21) or apharmaceutically acceptable equivalent.
 13. The composition of claim 8,wherein: X is oriented meta relative to C-1; and Y is oriented metarelative to X and meta relative to C-1.
 14. The composition of claim 13,wherein the compound of formula I is selected from the group consistingof:5-[4,5-dihydro-5-(4-hydroxyphenyl)-3-phenyl-1H-pyrazol-1-yl]-1,3-benzenedicarboxylicacid (23);5-(4,5-dihydro-3-methyl-5-phenyl-1H-pyrazol-1-yl)-1,3-benzenedicarboxylicacid (24); and pharmaceutically acceptable equivalents.